It is now well documented that cluster headaches are one of three primary headaches classified as trigeminal autonomic cephalagias.
Cluster headaches as defined by the 2004 International Headache Society Classification for Cluster Headache-II includes diagnostic criteria for cluster headaches as being (A) At least 5 attacks fulfilling the following criteria B-D, B) severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15-180 minutes if untreated, C) headache accompanied by at least one of the following i) ipsilateral conjunctival injection and/or lacrimation, ii) Ipsilateral nasal congestion and/or rhinorrhoea, iii) ipsilateral eyelid edema, iv) ipsilateral forehead and facial seating, and v) ipsilateral miosis and/or ptosis, C) a sense of restlessness and agitation, D) attacks having a frequency of 1 every other day to 8 per day and E) not attributed to any other disorder. Cluster headache sufferers are known to experience auras and shadows as do migraine sufferers, despite the 2 primary headache types being different in etiology (May A., Leone M., Afra J., Linde M., Sandor P. S., Eers S., Goadsby, P. J., EFNS (European Federation of Neurological Societies) “Guidelines On The Treatment Of Cluster Headache And Other Trigeminal Autonomic Cephalagias,” European Journal of Neurology 2006; 13: 1066-1077).
Cluster headaches are sub-categorized into episodic and chronic conditions. The International Headache Society defines the episodic condition as attacks fulfilling criteria A-E for cluster headache and at least 2 cluster headaches lasting 7-365 days and separated by pain free remission periods of >1 month, and the chronic condition as attacks fulfilling criteria A-E for cluster headache and attacks recur over >1 year without remission periods or with remission period lasting <1 month.
Neither etiology nor pathogenesis of this disorder is known. Numerous investigations have attempted to help clarify these mechanisms (Kudrow L., “Cluster Headache: Diagnosis and Management,” Headache (1979 April) 19(3):142-50; May 2006). Cluster headache is a rare disorder with an estimated prevalence of 0.1% or less depending on the country (Matharu M. S., Boes C. J., Goadsby P. J., “Management Of Trigeminal Autonomic Cephalagias And Hemocrania Continua,” Drugs 2003; 63:1637-1677). It is the most severe of the primary headaches and the most severe form of headache known to medicine. It is often called a “suicide headache” because those experiencing the repetitive higher level pain headaches often have thoughts of suicide, and, there are cases of sufferers committing suicide both during a cluster headache attack and during intervals between cluster headaches. The pain of cluster headache is often described in such graphic terms as boring in reference to drilling into, tearing or burning, and with such descriptive analogies as a “hot poker in the eye” or as if “the eye is being pushed out” (Capobianco D. J., Dodick D. W., “Diagnosis And Treatment Of Cluster Headache,” Semin Neurol 2006; 26:242-269; Nelson, R. F., “Cluster Migraine—An Unrecognized Common Entity,” Canadian Medical Association Journal, Nov. 7, 1970, Vol. 103, 1026-1030). Pacing, walking, sitting and rocking during the attack are activities which are considered pathognomonic of this disorder (Kudrow 1979). Approximately 93% of cluster headache sufferers report being restless during attacks resulting in behaviors such as pacing with the intense pain resulting in irrationality, violence and head banging (Blau, J. N., “Behaviour During A Cluster Headache,” Lancet (Sep. 18, 1993) 342(8873):723-5). It is not uncommon for cluster headache sufferers to fall asleep in place immediately after a severe cluster headache even with abortive or preventative medication being taken due to total exhaustion from dealing with the attack. Cluster headache patients, depending on the number of headaches per day and level of pain, may have high absentee rates from work or have to go on disability.
While the literature states that cluster headache sufferers may have on average from 1-3 headaches per 24 hour period, it is not unknown for those who have the chronic form of the condition to suffer as many as 16 cluster headaches a day for extended periods of time.
Abortive, transitional and preventative drugs and surgical procedures are used to manage cluster headaches. Many abortive and all preventative agents are used off label for cluster headache therapy i.e. their use for cluster headache therapy is not authorized by their official prescribing information or the Regulatory authorities but is used on the physicians initiative based on their individual conclusions regarding safety and efficacy.
Neither the etiology or mechanism by which the abortive and preventative drugs work in cluster headache is fully understood. Notably, none of the preventative medicines used in cluster headache are given on the basis of proven theoretical background. Their use is purely based on empirical evidence. (May A., “Cluster Headache: Pathogenesis, Diagnosis And Management,” Lancet 2005: 366: 843-855).
The goal of abortive therapy for cluster headache is fast, effective and consistent relief. Acute treatments of choice include 100% oxygen at 7 l/min to 15 l/min, Sumatriptan at 6 mg injected subcutaneously, zolmitriptan at 5 or 10 mg administered nasally and injectable dihydroergotamine. For the treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7 l/min over 15 minutes and 6 mg of subcutaneous Sumatriptan are drugs of first choice (Ekbom K., Hardebo J. E., “Cluster Headache: Aetiology, Diagnosis And Management,” Drugs (2002) 62(1):61-9; May 2006)
Transitional therapy is used to suppress headache while long term preventative therapy is introduced and titrated to an effective therapeutic dose. A number of drugs such as Prednisone have been used for this purpose.
Preventative agents include verapamil, lithium carbonate, valproic acid, methysergide, daily ergot and the anti epileptic drugs topiramate and gabapentin, each of which was originally developed for therapeutic use conditions other than cluster headache. In the prophylactic or preventative treatment, verapamil is a first option (Ekbom 2002, May 2006). Although cluster headache is clinically and diagnostically distinct from migraine, many of the same pharmacologic agents are used in their management.
It is also not uncommon for cluster headache sufferers with extreme pain to take opioids such as morphine.
The result is that cluster headache patients are often taking what may be called a pharmaceutical cocktail of therapies, which in the non-oxygen abortive triptans, preventatives and opioids can separately, let alone together, generate potential adverse effects, especially at the cluster headache dosing levels which often far exceed the on-label use recommendation for these drugs. An example is the commonly used abortive subcutaneously injected sumatriptan and the commonly used preventative drug verapamil that are taken by many patients and where each has potential adverse cardiac effects.
Destructive or invasive surgical interventions reported in the literature as therapy for cluster headache include application of glycerol to the trigeminal ganglion, radiofrequency rhizotomy of the trigeminal ganglion, gamma knife surgery to the trigeminal nerve, trigeminal tractotomy, trigeminal sensory nerve root section, surgical section of the nervus intermedius, combinations of nerve section decompression of the facial nerve, endoscopic spheno-palatine ganglion blockage with lidocaine and corticosteroids, and radiofrequency lesions of the pterygopalatine ganglion. The reported complications from such procedures include death, permanent neurological impairment, including corneal anesthesia which can lead to visual loss, anesthesia dolorosa, jaw deviation and cluster attacks switching sides after a unilateral lesion has been made. (Burns B., Watkins L., Goadsby P. J., “Treatment Of Medically Intractable Cluster Headache By Occipital Nerve Stimulation: Long-Term Follow-up Of Eight Patients,” Lancet (Mar. 31, 2007) 369(9567):1099-106; Rozen T. D., “New Treatments In Cluster Headache,” Current Neurology and Neuroscience Reports, 2002: 2: 114-121; Rozen T. D., “High oxygen Flow Rates For Cluster Headache,” Ltr to Editor August 2004 Neurology 63, 593; May 2006; Pascual J., Lainez M. J. A., Dodick D., Hering-hanit R., “Antiepileptic Drugs For The Treatment Of Chronic And Episodic Cluster Headache: A Review,” Headache 2007: 47:81-89; Rapoport A. M., Mathew N. T., Silberstein S. D., Dodick D., Tepper S. J., Sheftell F. D., Bigal M. E., “Zolmitriptan Nasal Spray In The Acute Treatment Of Cluster Headache: A Double Blind Study,” Neurology 2007; 69; 821-826).
These surgical procedures, while sometimes providing some period of relief from cluster headache, or a reduced level of pain, are often employed incremental to some form of continued oxygen or other abortive and preventative therapy, either at the same or reduced need levels immediately after the procedure or for some time thereafter, where the cluster headache sufferer may be free of attacks prior to the attacks then resuming.
Even to a lay person it should appear obvious that an unmet medical need exists for a therapy that is both fully safe and highly efficacious and which can reduce the impact of cluster headaches on the sufferers physical and psychological quality of life.
While a general vascular theory once also prevailed regarding cluster headache, this has been superseded by recognition that neurovascular factors are more important (May 2005).
The hypothalamus is thought to play a key role in the cluster headache condition (May 2005). It has been suggested that the primary defects in cluster headache are located in regulating centers in the anterior hypothalamus. There are several observations to support such a hypothesis. Alterations in biological rhythms of hormone secretion have been recorded, notably regarding cortisol, prolactin and testosterone, both during active periods and in clinical remission. The pineal sleep hormone melatonin is a biological marker of hypothalamic function and the circadian system, and its secretion has also been shown to be altered in cluster headaches (Ekbom 2002). Recent findings by positron emission tomography of an increased blood flow indicate vasodilation during attacks in the hypothalamic grey area on the painful side (May A., Bahra A., Buchel C., Frackowiak R. S., Goadsby P. J., “Hypothalamic Activation In Cluster Headache Attacks,” Lancet, Jul. 25, 1998, 352 (9124):275-8) and the structural changes in the same area (May A., Ashburner J., Buchel C., McGonigle D. J., Friston K. J., Frackowiak R. S., Goadsby P. J., “Correlation Between Structural And Functional Changes In Brain In An Idiopathic Headache Syndrome, Nat Med (1999 July) 5(7):836-8) lend further support to a central hypothalamic origin of the disease.
Magnetic resonance imaging angiographic studies and conventional carotid angiography have demonstrated a dilated intracranial segment of the internal carotid and ophthalmic arteries on the painful side during or outside attacks. This loss of vascular tone is believed to result from a defect in sympathetic peri vascular innervation. The same nerves run to the eye, giving rise to the miosis and ptosis seen during attacks (Ekbom 2002).
However, most now consider the attack to also be associated with local dilatation of the extracranial vessels in the regions supplied by branches of the external carotid artery. According to Friedman A. P., Mikropoulos H. E., “Cluster Headaches,” Neurology (1958 September) 8(9):653-63 and Wood E. H., Friedman A. P., “Thermography In Cluster Headache,” Res. Clin. Stud. Headache (1976) 4:107-111, this is suggested by the fact that during an attack one observes (1) a dilated temporal artery in some cases, (2) injection of conjunctiva and congestion of nasal mucosa, (3) local rise of skin temperature, (4) reduced ache on compression of the temporal artery and (5) a favorable response to vasoconstrictor agents. Horton (Horton B. T., “Histaminic Cephalgia: Differential Diagnosis and Treatment,” Proc Staff Meet Mayo Clin May 30, 1965 31(11):325-33) had found that compression of the common carotid artery and sometimes the temporal artery frequently gave prompt relief in the first stages of an attack. Horton considered that the attacks arose through local dilatation of branches of the external carotid artery. Kunkle (Kunkle E. C., “Clues In The Tempos Of Cluster Headache,” Headache (1982 July) 22(4):158-61) in a few patients, observed that the pain was eased during compression of the ipsilateral temporal artery
Extracerebral Flow Index (EFI) is an index of skull, scalp, muscle and skin tissue flow or volume. Sakai F. and Meyer J. S., “Abnormal Cerebrovascular Reactivity In Patients With Migraine And Cluster Headache,” Headache, 1979 19: 257-266, reported that in cluster headache patients tested during the headache interval when EFI values were increased (12.5+/%0.5%) indicating vasodilation, 100% oxygen inhalation caused a diffuse and excessive reduction of the EFI values (7+/−2%), indicating vasoconstriction. Friedman 1958 reported that most of the cluster headache causal theories seem to agree that we are dealing with periodic attacks of local dilatation of extracranial vessels in areas mainly supplied by the branches of the external carotid arteries. In support of the hypothesis of vasodilation are the distended temporal artery in some of the cases, the injection or even bloodshot appearance of the eye, the congestion of the nose, the local increase of the skin temperature, the occasional relief upon compression of the temporal or carotid artery and the usual good response to vasoconstrictive agents. Also in favor of the theory that dilation of extracranial vessels is responsible is the fact that since epinephrine does not constrict the intracranial vessels, the relief it gives in studies during such attacks must be due to the vasoconstriction of extracranial vessels. Friedman also referred to Kunkle 1982 who suggested that there is probably an increased susceptibility of the carotid artery of cluster headache patients to diverse vasodilating agents, and that this might be the reason for induced headache by histamine or alcohol. Drummond P. D., Anthony M., “Extracranial Vascular Responses To Sublingual Nitroglycerin And oxygen Inhalation In Cluster Headache Patients,” Headache (1985 March) 25(2):70-4, found that extracranial blood vessels on the symptomatic side of cluster patients were particularly susceptible to the vasodilator effect of nitroglycerine and to the vasoconstrictor influence of oxygen.
The intense debilitating pain of a cluster headache is in part theorized to be caused by the dilation of blood vessels which in part creates pressure on the trigeminal nerve. Nitroglycerine, a potent vasodilator, is a pro drug for nitric oxide, which can activate the trigeminal vascular system. 1 mg of Nitroglycerine administered sublingually was used as a provocative agent in 38 males with cluster headache and an attack was elicited 100% of the time if the patient was tested during the course of a headache period (Ekbom K., “Nitroglycerin As A Provocative Agent In Cluster Headache,” Arch Neurol (1968 November) 19(5):487-93). An increased sensitivity to vasodilator stimuli was therefore seen, and it was reported that attacks may be triggered by alcohol, histamine or nitroglycerine, with onset occurring after an interval of 30 to 50 minutes after intake. This time latency before an expected attack is of great interest as regards the underlying mechanisms. Nitroglycerin is a donor of nitric oxide and it was deemed tempting to believe that a local hypersensitivity to vascular effects of NO is one part of a chain of events that leads to a cluster headache attack following critical disturbances of the autonomic balance. Activation of the trigemino-vascular system and cranial autonomic parasympathetic reflexes may explain the pain and the autonomic features of cluster headache (Ekbom 2002).
A number of observations have indicated that there is vasodilation of the ipsilateral ophthalmic artery during a cluster headache attack. These include increased corneal indentation, pulse amplitude, intraocular pressure and skin temperature around the eye, as well as decreased blood flow velocities on ultrasonography. Magnetic resonance angiography performed during spontaneous attacks of cluster headache revealed marked dilation of the ophthalmic artery ipsilateral to the pain (Capobianco 2006). In a study of 112 patients with cluster headache, Wood 1976 found that islands of hypothermia were in the medial supraorbital area supplied by extracranial branches of the internal carotid artery (ophthalmic terminations). Drummond 1985 reported that when 100% oxygen was administered through a plastic mask at the rate of 10 liters per minute for at least 10 minutes, it produced significantly greater reduction in supraorbital pulsations on the symptomatic side in patients with headaches. Decreases in both arterial territories following oxygen inhalation were significantly greater during cluster headache than between cluster headaches or than in control subjects. 15 of 16 cluster headache patients reported at least some relief after breathing 100% oxygen for 10 minutes, the headache subsiding almost completely in 12 patients after 15 minutes. Changes in pulse amplitude of the superficial temporal artery pulsations on the symptomatic side recorded after 10 minutes of oxygen inhalation indicated the amplitude decreased in 15 of the 16 patients studied and averaged 30%.
Clinical observations of cephalic vascular changes accompanying typical cluster headache attacks have been consistently reported (Ekbom 1975).
While oxygen is effective in aborting a cluster headache the mechanism of the effectiveness of oxygen in treating cluster headache is not understood and the percentage of cluster headache sufferers who experience successful oxygen therapy, especially chronic sufferers over the age of 50, leaves much room for improvement. Reductions in cerebral blood flow, cerebral vasoconstriction, activation of the descending inhibitory neurons from the brainstem and an abnormal chemo receptor sensitivity in cluster headache have been suggested. (May 2005)
Smith reported in 1966 that his results support the view that oxygen tension may play a major role in autoregulation of blood flow. (Smith D. J., Vane J. R., “Effects Of Oxygen Tension On Vascular And Other Smooth Muscle,” J Physiol (1966 October) 186(2):284-94). Evidence for a direct vasoconstrictive effect of oxygen on cerebral blood vessels in vitro has been reported. As is well known and accepted by those versed in the art, Kety S. S. Schmidt C. F., “The Effects Of Active And Passive Hyperventilation On Cerebral Blood Flow, Cerebral Oxygen Consumption, Cardiac Output, And Blood Pressure Of Normal Young Men,” J Clin Invest (1946 January) 25(1):107-19, showed that in young men there is a 59% increase in CBF in response to 5% carbon dioxide. Kety S. S., “Blood Flow And Metabolism Of The Human Brain In Health And Disease,” Trans Stud Coll Physicians Phila (1950 December) 18(3):103-8, reported that the most remarkable observation in patients with cluster headache was the excessive cerebral and cranial vasomotor responsiveness to 100% oxygen inhalation during cluster headaches. In healthy young male volunteers, Kety had found using his method that 100% oxygen was reported to decrease cerebral blood flow, (hereinafter referred to as CBF) by approximately 13%. Norris J. W, Hachinski V. C., Cooper P. W., “Cerebral Blood Flow Changes In Cluster Headache,” Acta Neurol Scand (1976 October) 54(4):371-4 reported increased CBF values in a patient during a cluster headache attack. Sakai F., Meyer J. S., “Regional Cerebral Hemodynamics During Migraine And Cluster Headaches Measured By The Xe133 Inhalation Method,” Headache 1978 18:122-132, in an extensive study, presented CBF findings from contralateral and ipsilateral hemispheres. During the cluster attack there was a significant increase in CBF in the contralateral hemisphere even greater than that for the ipsilateral side. Later Sakai 1979 assessed cerebral vasomotor responsiveness using Xe 133 generated serial measurements of regional CBF during the steady state and during either 5% carbon dioxide inhalation, voluntary hyperventilation or 100% oxygen inhalation, also expressed as states of hypercapnia, hypocapnia or hyperoxia, in groups of patients with either migraine or cluster headache. Normal volunteers of both sexes showed a reduction of Fg, where Fg is CBF in gray brain matter, by 9.4+/−5.4%, correlating with Kety's earlier report. Sakai reported the cerebral vasoconstrictive response to 100% oxygen inhalation showed a diffuse and excessive reduction on the headache and non-headache side compared to normals and with migraineurs. The 100% oxygen inhalation also provided prompt and notable relief of headache. Precisely why an excessive cerebral vasoconstrictive response occurs during 100% oxygen breathing in patients with cluster headache, but not in migraine headache, is not fully understood. Differences in the disorder of cerebral vascular receptor sites in cluster headache and migraine headache is the suspected explanation. Apparently the effect of hyperoxia on catecholamine, serotonin, and possibly other vascular receptors, is excessive in patients with cluster headache. Apart from the direct oxygen effect on cerebral vessels influencing their neurotransmitter receptors, another possibility which may contribute to the resulting vasoconstriction is the Pasteur effect, whereby the cerebral tissue lactate levels vary inversely with the cerebral PO2 levels, the higher the PO2, the lower the tissue lactate and CBF. In summary, it has been show by these authors that increased PO2 levels potentiated the constrictive effect of catecholamines and 5 hydroxytryptamine on skeletal muscle, which may account for the effect of 100% oxygen breathing on CBF.
Kobari M, Meyer J S, Ichijo M, Kawamura J., “Cortical and Subcortical Hyperfusion During Migraine and Cluster Headache Measured by Xe CT CBF,” Neuroradiology 1990 32: 4-11, measuring CBF with high resolution color coded images produced by stable Xenon enhanced CT imaging, found that during cluster headache attacks, local CBF values are markedly increased bilaterally in all cerebral cortical and subcortical regions excluding the occipital cortex. Cerebral hyperperfusion during cluster headaches is observed in the same regions as seen in migraine headaches, but appeared to be greater in degree and more prominent ipsilateral to the head pain. Local CBF values for cerebral cortex, basal ganglia and white matter of both hemispheres were markedly increased during attacks of headache, exceeding those seen in migraine. They also tended to be greater on the side of the headache and associated with cephalic autonomic signs. The closer correlation between the side of the headache and local CBF increases suggested involvement of the trigeminal nerve in the occurrence of cerebral hyperfusion.
This was followed by Kawamura J., Meyer J. S., Terayma Y., Weathers S., “Cerebral Hyperemia During Spontaneous Cluster Headaches With Excessive Cerebral Vasoconstriction to Hyperoxia,” Headache 1991 31: 222-227, measuring local cerebral blood flow in 3 dimensions using Xenon enhanced CT imaging during spontaneously occurring cluster headaches, during headache free intervals and immediately after terminating attacks by inhalation of 100% oxygen, found that CBF values for temporal cortex, basal ganglia and subcortical white matter were increased. Immediately after terminating attacks of cluster by 100% oxygen for five minutes, CBF values for temporal cortex and basal ganglia became significantly decreased below normal values in five patients with spontaneously occurring cluster headache. Prompt relief of head pain by inhalation of 100% oxygen was reported as associated with abolition of the hyper perfusion of both cortical and subcortical brain structures that occurs during spontaneously occurring cluster headaches and is followed by excessive cerebrovascular vasoconstriction. The conclusion reached was that rapid termination of head pain by hyperoxia associated with excessive cerebral vasoconstriction suggests that this vascular phenomenon is unique to cluster headaches and offers clues to its pathogenesis. The characteristic unilateral orbital and retro-orbital head pain is consistently ameliorated by digital compression of the carotid artery in the neck or 100% oxygen inhalation which is a potent cerebral vasoconstrictor.
In summary, it is accepted knowledge in the literature that as an abortive therapy for cluster headache, high levels of oxygen blood saturation lead to reduced cerebral hyperperfusion, high levels of cerebral vasoconstriction, reduce oxidative stress, and promote cellular respiration (Kawamura 1991; Cohen A. S., Matharu M. S., Burns B.1, and Goadsby P. J., “Randomized Double-Blind, Placebo-Controlled Trial Of High-Flow Inhaled Oxygen In Acute Cluster Headache,” International Headache Congress 2007), although the complete mechanism of the effectiveness of oxygen in treating cluster headache despite decades of literature is still not fully understood (Kudrow L. Response of Cluster Headache Attacks to Oxygen Inhalation. Headache 21: 1-4, 1981, May 2005).
It is important to state at this point that oxygen therapy as used to treat cluster headaches is not similar in mechanism or intended benefit to the use of oxygen in respiratory therapy. In traditional respiratory therapy, for example of Stage 3 or Stage 4 chronic obstructive pulmonary disease also known as COPD, the objective is long term, continuous and non stop oxygen therapy in order to raise oxygen saturation above a minimally required level in order to sustain life and, better yet, provide some semblance of an active vs. sedentary life for the outpatient or home care patient, and at a relatively normal respiration rate. The patient, especially in Stage 4 of COPD, is usually on continuous oxygen therapy 24 hours a day 7 days a week. A low arterial blood oxygen saturation of 88 out of a maximum value of 100 taken at rest versus a normal arterial blood oxygen saturation in the low to mid 90's is more or less a universally recognized requirement in order to qualify for reimbursement of oxygen based respiratory therapy.
In cluster headache therapy the primary objective of oxygen use is to saturate the blood and raise the oxygen level as close as possible to 100% in as short a time as possible, to cause cerebral vasoconstriction which it has been found results in the cluster headache being aborted. This can occur during symptoms just before or during an actual cluster headache. The cluster headache sufferer is not at rest nor breathing normally when using oxygen for therapy, but is hyperventilating from both the hyperactivity and the pain caused by a cluster headache. This also impacts the volume of oxygen consumed by a cluster headache sufferer vs. a patient who has COPD in late Stage 3 or 4 within the same time frame. Finally, while such a COPD patient tends to be on oxygen full time or near full time, a cluster headache sufferer only uses oxygen just before, at the start of or during a cluster headache. There are always intervals between cluster headaches, and, there may be long intervals between cluster headaches when the sufferer does need or use oxygen.
First cited by Horton in 1956, the use of oxygen therapy has since become the standard treatment in relieving headache attacks. 100% oxygen inhalation administered at a continuous flow rate of 7 to 12 l/min for 15-20 minutes with a non-rebreathing mask has been most cited as being effective in approximately 50% to 80%, but more commonly a cited figure of 70% of subjects, and often as being effective within 5 minutes, as first cited by Kudrow 1981 and Fogan L., “Treatment of Cluster Headache. A Double Blind Comparison of oxygen vs. Air Inhalation,” Arch Neurology 1985: 42: 362-363, and then by Ekbom in 2002 (Ekbom K, Hardebo J E. Cluster Headache: Aetiology, Diagnosis And Management. Drugs (2002) 62(1):61-9). Importantly, there is no linking of the abort time to the severity of the cluster headache. Kudrow 1981 and Fogan 1985, as well as all virtually all textbook and other articles on cluster headache treatment instruct patients to use this method and the continuous flow rate range. The rationale behind this prescribed oxygen flow rate is unknown, but this has become doctrine since the Kudrow study (Rozen 2002). Additional references evidencing oxygen efficacy as an abortive agent for cluster headache include Ekbom K., “Treatment Of Cluster Headache: Clinical Trials, Design and Results,” Cephalagia 1995 Suppl. 15, 33-36; Dodick D. W., Rozen T. D., Goadsby P. J., Silberstein S. D., “Cluster Headache,” Cephalalgia (2000 November) 20(9):787-803; Rozen 2002, May 2006, Cohen A S, Matharu M S, Burns B1, and Goadsby P J. “Randomized Double-Blind, Placebo-Controlled Trial Of High-Flow Inhaled Oxygen In Acute Cluster Headache” International Headache Congress 2007 and Balasubramaniam R., Klasser G. D., “Trigeminal Autonomic Cephalagias: Part 1: Cluster Headache,” Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 104:345-58. It has been reported that subjects respond to higher flow rates of 15 l/min after not responding to traditionally used flow rates of 7 l/min. (Rozen 2004 letter to editor), and, the higher flow rates have been shown in controlled studies to be safe and effective (Cohen 2007). As recently as 2004, however, it was stated that there is no evidence that more than 15 l/min of continuous flow provides any incremental benefit in aborting a cluster headache (Rozen 2004). As suggested by this author in a private communication to the inventors, this perception is in large part generated due to Neurology and headache specialty training versus training received by a Pulmonologist regarding available oxygen delivery systems and methods and the multi decade accepted standard of care consisting of 7-15 l/min continuous flow non-rebreathing mask systems.
In some patients, oxygen is completely effective at aborting an attack if taken when the pain is at maximal intensity, whereas in others the attack is only delayed for minutes to hours rather then completely alleviated. (Rozen 2002). However, it has been reported by several authors (Kudrow 1981, Matharu 2003, Rozen 2002) that a cluster headache attack can recur shortly after discontinuation of oxygen even if there had been a complete abortive response. This is now commonly called a re-attack. Using the above method which has become the standard of care regarding use of oxygen to abort a cluster headache, up to 25% of patients note that oxygen simply delays the attack for minutes to hours rather then completely aborting it. (Matharu 2003)
Favier I., Haan J., Ferrari M. D., “Chronic Cluster Headache. A Review,” J Headache Pain 2005 6:3-9, reported the success rate with oxygen using the above method is greater among patients with episodic rather than chronic cluster headache, with Kudrow 1981 previously reporting that 75% of patients obtained significant relief from cluster pain, with treatment success defined as complete or almost complete cessation of head pain within 15 minutes for at least 7 of 10 attacks, with the greatest benefit (92.9%) being found among episodic patients under 50 years of age and the least benefit (57%) being found among chronic patients over 49 years of age.
In summary, the consensus in the literature is that success of the treatment to abort a cluster headache with oxygen is related to high continuous flow rates of 7 liters to 15 l/min, high oxygen concentration desirably as close to 100% oxygen as possible, and allowing a reasonable amount of time for inhalation.
A major deficit in the existing literature on the use of oxygen to abort a cluster headache, is that efficacy and time to abort is given in terms of sex, age and other criteria, but no relationship is given between the level of a cluster headache in terms of pain, for example, using the Kip scale, which is broadly used to describe cluster headaches in the US patient community and to some degree in the medical community, and the efficacy of oxygen and time to abort. Solicited cluster headache sufferer input indicate that there is a direct correlation between Kip or pain level of a cluster headache and abort time when using oxygen. An added factor not always recorded or reported is when oxygen therapy was initiated, i.e., at the start of symptoms, after the start of an actual attack or well into the attack.
Several sources of oxygen exist that may be used to generate the continuous flow l/min rates described in the literature and representing the current standard of care for aborting a cluster headache with oxygen. The most common source of continuous oxygen flow is an oxygen regulator with a flow meter control that is attached to a compressed gas cylinder of medical oxygen. Liquid oxygen (LOX) reservoirs are used in some European countries. However, only a few models have possible flow rates as high as 15 l/min and can only provide this flow rate for a limited period of time. Portable LOX units use heated manifolds to convert LOX to oxygen gas. The heated manifold LOX to gas conversion capacity is related to manifold size and for portability battery size and weight relative to power consumption required to generate the needed manifold heating. Due to LOX system cost and typical reimbursement policies, cluster headache sufferers may have only one portable LOX unit which is usable for perhaps aborting 1-2 cluster headaches that they need to keep refilling at home from a reservoir. However, they can have multiple compressed gas cylinders of various sizes, including those considered carryable or portable, which provide flexibility and sufficient oxygen for numerous cluster headache attacks. Oxygen concentrators are rarely used due to their typically low continuous flow volumes of 5 l/min or less, with some more expensive systems providing 10-15 l/min. In addition, oxygen concentrators only generate 93% mole percent oxygen when a source of 100% oxygen is most desirable for effective cluster headache therapy.
The devices historically tried and used to delivery continuous flow oxygen inhalation to the cluster headache sufferer primarily include disposable nasal cannula, low to medium oxygen concentration oxygen masks and non-rebreathing high oxygen concentration mask systems with one way valves on the mask itself and a 1 liter reservoir bag. It is important to emphasize that these 3 oxygen delivery systems were and are produced and intended for use in respiratory therapy for COPD and other pulmonary ailments, and not for cluster headache therapy, for which they have been adopted.
In respiratory therapy applications, patients use relatively low continuous flow rates with <3 l/min being typical, in the course of normal sedentary or walking respiration where supplemental oxygen is required. As COPD increases in severity, the patient usually leads an increasingly sedentary lifestyle even though some degree of exercise is encouraged, and requires more oxygen in the form of a higher continuous flow rate, but is still breathing at a relatively normal rate in terms of breaths per minute. As evidenced by the upper continuous flow limit of 15 l/min of just a few LOX systems and oxygen concentrators but most providing a much lower maximum flow rate, higher continuous flow rates are not used in outpatient or homecare self administered respiratory therapy.
Nasal cannula and low to medium concentration oxygen masks result in a high degree of dilution of delivered oxygen with air, such that actual inhalation of anywhere at or near 100% oxygen is impossible. These are no longer prescribed by physicians or used by cluster headache sufferers either schooled in the art, aware of the literature or participating in patient organization support groups.
As broadly noted in the US and European medical literature, a continuous flow non-rebreathing mask with a 1 liter reservoir bag is the standard of care delivery device for abortive oxygen therapy. When using such a non-rebreathing mask system, key factors in achieving adequate cluster headache therapy include continuous flow oxygen rate, mask volume, reservoir bag volume, ventilatory resistance and tightness of mask fit. These are all variables in delivering at or near 100% oxygen.
Traditional non-rebreathing masks systems, originally designed for respiratory therapy, use a head strap to hold the mask on the patients head. This is because of the extended periods of use, which can be 24 hours a day and 7 days a week for late Stage 3 or Stage 4 COPD patients. A tight facemask seal is not always needed or achievable due to slippage or stretching of the elastic band head strap on disposable non-rebreathing masks systems worn for such extended periods of time. Because the typical non-rebreathing mask system is disposable and intended for respiratory therapy use where patients generally use a head strap the one way valves on these masks are made of non durable thin rubber, plastic, vinyl or silicone. They are about the size of a nickel coin, with the thickness of a business card, and are mounted on the mask over a pattern of small holes. The design is supposed to allow exhaled gases to escape, but not allow air to enter. The reliance on a head strap to hold the mask in place by respiratory therapy patients leaves the mask itself relatively unflexed and the valves intact and functional, whereas cluster headache patients typically grabbing the mask to hold it as tight as possible against their face and flexing the mask by doing so can lift or pop the valves off the mask surface exposing the holes in the mask beneath the valve leading to air entering the mask and diluting incoming oxygen from its source during every inhalation.
In the US, it is not common practice among cluster headache sufferers to use a head strap to hold a non-breathing mask in place for three reasons. First, the elastic head strap touches a sensitive part of the head during a cluster headache which is an important factor as many cluster headache sufferers experience skin surface allodynia during an attack. Second, the mask with just the head strap does not provide a tight enough facial seal to assure minimization of room air leaking into the mask. Cluster headache sufferers therefore tend to hold the mask tightly against their faces to create a tight seal and maximize the oxygen concentration being delivered. They also hold the mask itself tightly and roughly due to the intense pain being experienced and physical activity during a cluster headache attack, such as pacing back and forth or rocking back and forth while sitting. The mask is thus highly flexed and the valves may pop off or be partially gripped or torn off the mask, leading to a high degree of dilution of the continuous flow oxygen input into the mask with room air during inspiration. Finally, many cluster headache sufferers fall asleep from exhaustion immediately after an attack is over. They are advised by experienced cluster headache sufferers not to use a head strap but to hold the mask, so that if they fall asleep after an attack is over they are not at risk of having a non-breathing mask system over their nose and mouth if the oxygen cylinder it is attached runs out of oxygen while they are asleep.
The dose of oxygen the patient receives with a standard non-breathing mask with a reservoir bag is controlled by the rate of flow entering the mask circuit, which is mechanically controlled by a compressed gas regulator and its flow meter setting. Cluster headache sufferers tend to hyperventilate during the initial phase of a cluster headache due to pain, with hyperventilation increasing as the pain level and related physical activity, such as pacing, increases. Whether a cluster headache sufferer breathes normally, moderately fast or hyperventilates, the rate of oxygen flow into the mask remains the same. It is quite easy for anyone to self demonstrate using such a non-rebreathing mask that if one slowly hyperventilates at 30 breaths per minute or fast hyperventilates at 60 breaths per minute at 7 l/min continuous flow the reservoir bag collapses. It barely stays inflated if one increases the continuous flow input to 15 l/min.
This lack of sufficient incoming oxygen flow contributes to carbon dioxide accumulation in the mask from exhaled breath prior to the next breath, which leads to an unacceptable amount of carbon dioxide mixing with the oxygen entering the mask from its source. Carbon dioxide is well known to be a potent vasodilator in even small concentrations, such as 5-6%. Indeed, even a minute increase of about 0.25% alveolar carbon dioxide will lead to a 100% increase in pulmonary ventilation rate (U.S. Navy Flight Surgeon's Manual, 1991). MRI imaging studies using noninvasive continuous arterial spin-labeled-perfusion MRI have shown that 6% carbon dioxide in oxygen can substantially counteract the vasoconstrictive effects of the 94% oxygen in an inhaled mixture and reference the fact that breathing 100% O2 at 1 atmosphere absolute (ATA) is known to be associated with a decrease in CBF (Floyd 2003). The effect of carbon dioxide is also supported by functional MRI imaging using BOLD or blood oxygen level dependent pulse sequences whereby it was reported that carbon dioxide increases the cerebral blood volume and cerebral blood flow within the brain by bringing about the vasodilation of arterioles and small arteries. And, in young men there is a 59% increase in CBF in response to 5% carbon dioxide (Krozyck G., “Cerebral Vascular Reactivity Evaluation by Bold fMRI,” University of Toronto Medical Journal, Vol 79, number 1, December 2001, 18-21).
These flow rate levels vs. the breathing rate plus inspiratory oxygen volumes required by the cluster headache sufferer in the lead up to and during a cluster headache also result in considerable ventilatory inspiratory resistance, as the cluster headache sufferer is trying to inhale a volume of gas that is not available in the non-breathing mask due to its sole source of oxygen being the fixed continuous flow rate entering the mask from the oxygen gas source. The difficulty in inhaling from the non-rebreathing mask system that is not sufficiently or completely filled between the breaths of someone hyperventilating due to pain and physical activity leads to increased anxiety and further and or prolonged hyperventilation. The cluster headache sufferer can be gasping for breath trying to inhale volumes of oxygen or gas not available within the non-rebreathing mask system due to the fixed input continuous flow from the oxygen source. The result is that the cluster headache sufferer may be sucking in air through faulty portions of the masks facial seal by sheer negative pressure generated by inhaling, if not gasping, when no gas volume is left in the mask, or, lifting the mask to inhale room air out of panic in their mental state during a severe cluster headache. In either case, the result is a lowering of the blood oxygen saturation level that breathing 100% oxygen is supposed to achieve in order to generate an abortive therapeutic benefit and a defeat of the essential basis of the therapy.
The collapse of non-mask system reservoir bags when using 7 l/min is evidenced in published video studies of cluster headache attacks because the incoming oxygen volume has been exceeded by the inhalation rate of breath and volume per breath demand. The result is the patient inhaling a concentration of exhaled carbon dioxide along with new incoming oxygen from the continuous flow source, and, any air that leaks in through the mask facial seal due to negative pressure generated by the cluster headache sufferer gasping, decreasing the effectiveness of what would have been 100% oxygen, and therefore greatly diminishing the effectiveness of the therapy.
In summary, a hyperventilating and physically active cluster headache sufferer during an attack can require and be attempting to inhale high flow rates and volumes of oxygen that cannot be met by the standard of care fixed continuous flow rates of 7-15 l/min using a non-rebreathing mask with valves and a 1 liter reservoir bag. All of the above is an example of how the historical and current standard of care use for cluster headache therapy of 7-15 l/min continuous flow with a standard non-breathing bag designed for respiratory use creates a severely problematic therapy regimen for aborting a cluster headache and doing so in as little a time as possible.
In light of the above aspects of the use of a non-breathing bag, Tinits P., “Oxygen Therapy and Oxygen Toxicity,” Annals of Emergency Medicine 12:5, May 1983, 321-328, cited that a non-rebreathing reservoir mask has been reported to deliver an FiO2 of about 90% at 8 to 15 l/min in respiratory therapy patients. A recent study by Standley in 2007 (Standley T, 2008, University of Cambridge, private communication to Linde Gas LLC, not yet published), measured oxygen present in a standard non-rebreathing mask and FiO2 over an initial period of approximately 3 minutes with a normal breathing rate. A continuous oxygen flow rate into the mask of 6 l/min resulted in an oxygen concentration in the mask system that was between 30 and 40%, for 9 l/min was between 40% and 50%, at 12 l/min was between mid 40 and 60% and at 15 l/min was between 50 and 60%. FiO2 clearly increased with increased flow rate but was also far below the 100% oxygen being fed into the mask from a source. Therefore, even a “high concentration non-rebreathing masks system,” supposedly intended to deliver close to an ideal 93% from an oxygen concentrator or 100% oxygen from a compressed cylinder or liquid oxygen reservoir source, significantly fails to do so. This is critical regarding the level of efficacy achieved with such masks in treating cluster headache with what is supposed to be 100% oxygen inhaled. Despite the above data concerning the less than 100% oxygen actually inhalable versus what is fed into the non-rebreathing mask, the literature broadly indicates that 7-15 l/min of oxygen flow into the mask is still effective in aborting cluster headache in the range of 70% of patients studied. Just as important relative to cluster headache use of a non-rebreathing mask system, this same study revealed that during hyperventilation with a standard non-rebreathing mask, the percent oxygen actually in the mask ranged from the high 30% to mid 70% range, with normal ventilation it ranges from the low 50% to low 80% range, and, with hypoventilation it ranges from the low 50% to high 80% range. Where it would be desirable in the case of a cluster headache attack for hyperventilation to result in rapid escalation of oxygen levels in the blood, less far less then 100% oxygen would actually be delivered using such a standard non-rebreathing masks system . . . which is the standard of care oxygen delivery device today for cluster headaches. While a mouthpiece was suggested in the study to be superior, use of a mouthpiece and the application of nose clips to prevent the dilution with air inhaled via the nose is difficult for many cluster headache sufferers at the start of an attack, and, the nose clips can generate claustrophobia/anxiety during an attack. In summary, it would appear that the assumptions in the past as to the efficacy of 100% oxygen being inhaled via a non-rebreathing mask were in fact false as while 100% oxygen was being fed into the mask less if not far less than 100% oxygen was actually being inhaled.
Therefore, while all of the literature assumes because 100% oxygen is being delivered into a non-breathing mask and that is what the patient is inhaling, it is in reality not the case, in particular when hyperventilation is involved which cluster headache sufferers routinely do but on a randomized basis while breathing oxygen during an attack. Despite this, oxygen has been proven to have value as an abortive agent.
A medical demand valve for oxygen delivery is traditionally a resuscitation device for use in acute emergency medicine that delivers oxygen via full face mask and is not a device historically used for repetitive therapy of a specific chronic condition and specifically not for any primary headache condition.
A medical demand valve for oxygen is similar in mechanical function to a SCUBA diver's regulator that delivers air or another mixed gas only as of the point in time when the user starts to inhale, i.e., it is not a continuous flow system. A SCUBA diver's regulator delivers air or special mixtures including but not limited to oxygen plus another gas such as helium or nitrogen intended to safely support life under water at various depths. A medical oxygen resuscitation demand valve is intended for use only with oxygen and out of the water. Several mechanical differences exist between medical demand valves for oxygen resuscitation delivery and SCUBA demand such as but not limited to the medical oxygen demand valve requiring a lower pressure on inspiration to activate the demand valve diaphragm, and a lower expiration pressure.
A medical oxygen demand valve delivers oxygen to the user as soon as they try to inhale from an attached mask or mouth tube. As the user starts to inhale the slight drop in pressure within the mouth piece or mask lifts a valve and starts the oxygen flow. If the user inhales more deeply, more oxygen will flow in response to the increased demand, hence the name demand valve. When using a medical oxygen demand valve, oxygen dosage is controlled by the respiration rate and tidal volume of the individual patient. Demand valves are connected directly to a high pressure source of oxygen such as a compressed gas cylinder of medical oxygen, which has a regulator with a 40-60 psi output connection.
A typical medical oxygen demand valve for resuscitation operates on 40-60 psi pressure and delivers from 140 to 160 l/min maximum rate of flow, depending on the vendor. This is substantially different from continuous flow non-rebreathing masks where the oxygen flow rate is controlled by (i) the flow meter on an oxygen source which in the case of compressed gas cylinders and available medical oxygen flow meters is a maximum of either 15 or 25 l/min; (ii) the maximum 15 l/min at 22 psi from just a critical few portable liquid oxygen sources for limited durations of time before the manifold freezes; and (iii) a maximum of 10 l/min sometimes up to about 30 psi but usually at a much lower psi depending on vendor concentrator model that also delivers only about 93% oxygen which for cluster headache therapy is neither desirable nor as effective as a 100% oxygen source.
The use of a medical oxygen demand valve making available up to 140 to 160 l/min for cluster headache oxygen therapy and therefore amply providing for even fast hyperventilation which would consume less than half that rate is not a current standard of practice. As previously noted, it has been reported that higher oxygen flow rates above 15 l/min have not been shown to benefit cluster headache patients refractory to standard oxygen therapy. (Rozen 2004) This is in part due to the lack of familiarity that physicians who treat cluster headache patients have concerning demand valve oxygen delivery equipment, and, their reliance on the known standard of care, i.e., the non-rebreathing oxygen mask system, as the device by which they evaluate higher flow rates which are continuous in nature, fixed by the rate of flow delivered by the available flow meters, and which suffer from the other non-rebreathing mask related deficits described herein. Therefore, the use of a demand valve and its ability if used according to a specific method to significantly improve oxygen therapy of cluster headache is novel and not intuitive to anyone schooled in the art of cluster headache therapy. In fact, oxygen demand valves have been available for decades and have never been cited in the large base of historical cluster headache literature as a potential device for oxygen therapy in cluster headache.
Applicants are personally aware of a handful of cluster headache sufferers using demand valves. In these cases, as far as applicants are aware, the use of a demand valve was not prescribed by the patients physician, the unit was directly purchased by the patient in used or new condition from an internet source, and is used (i) wholly for convenience, as it reduces preparation time for use of oxygen when a cluster headache starts; (ii) eliminates the need to continuously buy disposable non-rebreathing masks with reservoir bags; and, (iii) because they are believed to make it easier to breathe during a cluster headache because of the very high oxygen flow rates available versus a fixed and much lower continuous flow rate available from standard medical oxygen flow meters. Importantly, applicants are not aware that these users employed any specific method of use of the demand valve that significantly improves efficacy by reducing the abort time for a cluster headache or generates other benefits such as reduced re-attacks, reduced number of cluster headache attacks in general or reduced need for other abortives such as sumatriptan. They generally breathe using the demand valve with no particular method or pattern other then their respiratory rate and inhalation volume needs being met during a cluster headache generated by pain, hyperactivity and anxiety.
Although hyperbaric oxygen has been much discussed as a therapeutic option and success has been reported, in what is regarded as a definitive placebo controlled double blind crossover study in patients within episodic and chronic disease no significant prophylactic effect was obtained. (Nilsson Remahl A I, Ansjon R., Lind F., Waldenlind E.: “Hyperbaric oxygen Treatment Of Active Cluster Headache: A Double-Blind Placebo-Controlled Cross-Over Study,” Cephalalgia November 2002 22(9):730-9). Furthermore, hyperbaric oxygen therapy is not a practical form of abortive therapy since cluster headache sufferers have their headaches at home, at work, while shopping or otherwise located and need immediate access to therapy in order to achieve optimum relief. The scarcity and cost of use of hyperbaric oxygen systems at medical care facilities, the need for professional care givers specially trained in hyperbaric medicine to be present in order to operate them, the time it takes to get a patient into one, and, their high cost of use without reimbursement for cluster headache therapy, renders them also all but unusable for aborting a cluster headache.
No medical journal articles were found which discussed the use of an oxygen medical demand valve intended for emergency resuscitation use as a delivery device for cluster headache, nor therefore any specifically effective method of demand valve use. Three papers discussed demand valves in the context of those types of devices that provide small bolus doses of oxygen at points of inspiration equivalent to a relatively low continuous flow rate for respiratory therapy of COPD. An example of one of these papers is Rinow M. E., Alan R. S., “Effectiveness Of A New Oxygen Demand Valve In Chronic Hypoxemia,” Chest 1986. 90:2. 205-207, which describes an inspiratory demand valve that attaches to an oxygen source and delivers oxygen after the sensor detects a negative pressure through a standard nasal cannula. It describes the intended use as being for patients having chronic hypoxemia secondary to COPD and in the case of this paper is based on studying patients under resting conditions, and not conditions of hyperventilation. The objective of using the type of demand valve described in this paper, now known as a conserver and intended for low flow rates such as 3 l/min, is an efficacy equivalent to non stop continuous flow and savings on use and cost of oxygen, and not a significantly improved efficacy or change in the change in the basic nature of the condition.
In summary, no mention of a medical demand valve originally designed for acute emergency resuscitation as being used to deliver oxygen for cluster headache therapy was found in the medical literature, and no reference was found in the literature to a specific method of demand valve use that provides the significant benefits described in this application.
In addition to oxygen, the leading pharmaceuticals used as abortive therapies for cluster headache include subcutaneous injection sumatriptan, inhaled zolmitriptan and injected dihydroergotamine, with subcutaneous injection sumatriptan being the dominant current abortive.
Patients with chronic cluster headache respond well to the use of subcutaneous sumatriptan, but to a lesser extent than episodic patients. Chronic cluster headache patients responded more slowly than patients with episodic cluster headache (Favier 2005).
In double blind, placebo controlled trails, the HT1b/D agonist sumatriptan (6 mg injected subcutaneously) was effective in about 75% of all cluster headache patients in terms of being pain free in 20 minutes Sumatriptan injection appeared to be 8% less effective in chronic cluster than in episodic cluster (Rozen 2002). The recommended dose of subcutaneously injected sumatriptan according to its authorized package insert is 6 mg, with a maximum of 2 doses per 24 hours. It is also stated that subcutaneously injected sumatriptan should not be given to patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes, significant underlying cardiovascular diseases, ischemic cardiac syndromes such as angina pectoris of any type, all forms of myocardial infarction and silent myocardial ischemic. Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as transient ischemic attacks, and, there is a risk of myocardial ischemia and/or infarction. Although generally well tolerated, sumatriptan is contraindicated in patients with ischemic heart disease or uncontrolled hypertension. Caution must be exercised since cluster headache predominates in middle aged males who often have risk factors for cardiovascular disease, particularly tobacco abuse, which is present in up to 88% of cluster headache sufferers (Capobianco 2006). There is also some percentage of cluster headache sufferers who are needle phobic and for whom constant subcutaneous injections of sumatriptan are difficult if not impossible to pursue.
Chronic cluster headache sufferers in particular sometimes have many more than 2 cluster headache attacks a day. The result is that if they follow the package insert recommendations, only two of their daily cluster headaches can be treated with injectable sumatriptan. It is therefore not uncommon for in particular chronic extreme cluster headache sufferers to take more than the recommended daily dosage of Sumatriptan injection. The high cost of Sumatriptan is reportedly in the range of $125 to $175 per 2 doses. This presents a clear economic burden on cluster headache patients, especially given episodic sufferers may have attacks every day during an episode that can last for weeks or chronic sufferers may have attacks every day during a given year. Adding to this economic burden on the patient, is the fact that many insurers only provide coverage for up to 8 doses a month if they cover the use of the drug at all (Imitrex (subcutaneous sumatriptan injection) Utilization Management Criteria, Blue Cross Blue Shield North Carolina Web Site June 2008). It is well known to those familiar with the cluster headache sufferer community that they have learned to open and adapt the standard 6 mg injector drug carpule and use it for 2 doses of 3 mg each in order to extend the number of doses available and/or reduce their costs for the drug. It has been reported based on study results that use of 2 mg or 3 mg of subcutaneously injected sumatriptan is highly efficacious if used concomitantly with oxygen, with 3 mg injectable sumatriptan plus oxygen generating 74% efficacy with fewer side effects then the 6 mgm dose of Sumatriptan alone (Gregor N., Schlesiger C., Akova-Ozturk E., Kraemer C., Husstedt I. W., Evers S. “Treatment of Cluster Headache Attacks With Less Than 6 mg Subcutaneous Sumatriptan,” Headache (2005 September) 45(8):1069-72). However, the remaining high cost for injectable sumatriptan on a constant basis, day after day during an episode or ongoing for a chronic sufferer, whether using 3 mg or 6 mg per cluster headache, with or without insurance and co-pay, is still prohibitively high. Just two headaches on average a day, every day for a year for a chronic cluster headache sufferer, treated alone with 6 mg of subcutaneously injected sumatriptan, and a high level co-pay of $30 per 2 daily doses, can generate an out of pocket cost to the patient of over $10,950. For a cluster headache sufferer who does not have co-pay coverage, or, is limited to only 8 doses covered by co-pay per month which is not an uncommon practice by insurance carriers, an impossible financial barrier is raised to routine use of the drug by cluster headache sufferers. Patients have also reported to the leading cluster headache patient organization that health insurance companies are starting to drop them as clients because of their routine use of expensive subcutaneous sumatriptan injections. Due to subcutaneous injectable sumatriptan currently being the lead abortive pharmaceutical for cluster headache and as noted in the literature and above its very high cost and limited insurance coverage, a means of significantly improving the efficacy of a solely oxygen based therapy of cluster headache due to its much lower cost is desirable from a health economics viewpoint, and, from a financial affordability viewpoint for the individual patient. Zolmitriptan nasal spray at doses of 5 and 10 mg is effective and tolerable for acute treatment of cluster headache (Rapoport 2007). Zolmitriptan nasal spray also has a recommended limit of 2 doses per day as stated in its authorized package insert. The prescribing information includes reference to possible drug interactions, effect of oral contraceptives on plasma concentrations, and recommends that it not be taken if the potential user has heart disease or a history of heart disease, have had a stroke or problems with blood circulation, have taken sumatriptan, rizatriptan, or ergotamines within the last 24 hours, have taken MAO inhibitors for depression within the last two weeks, Serotonin reuptake inhibitors such as Paroxetine, Fluoxetine or Sertraline, or serotinin neurepinephrine reuptake inhibitors such as Duloxetine.
The calcium channel blocker verapamil is a leading preventative pharmaceutical used off label for cluster headache. A daily dose of 240 to 320 mg of verapamil is the established preventative treatment of choice in the prophylaxis of chronic and episodic cluster headache (May 2005). If a patient needs greater than 480 mg/day of verapamil, then an electrocardiogram is necessary before each dosage change to guard against heart block. It is not uncommon for cluster patients to need dosages as high as 800 mg/day to gain cluster remission. (Rozen 2002). A recent study indicated that high dose verapamil is an increasingly common preventative treatment in cluster headache. Side effects include atrioventricular block and bradycardia, although their incidence in this population is not clear. The report strongly recommend EKG monitoring in all patients with cluster headache on verapamil. (Cohen A S, Matharu M S, and Goadsby P J. Electrocardiographic Abnormalities in Patients with Cluster Headache on Verapamil Therapy. Neurology 2007: 69: 668-675).
Cluster headache sufferers are therefore primarily faced with the use of subcutaneous sumatriptan or inhalable zolmitriptan, which are effective but can only be used a limited number of times a day without risk of adverse effects in particular to the heart, and is extremely costly, plus verapamil at dose levels which can also impact the heart.
In summary, patients want simple self-administered drugs with high efficacy, a tolerable, rapid and consistent action and low cost. Those patients who have more than two cluster headaches a day need an abortive agent that can be used to abort as many cluster headaches as they have per day. Sumatriptan is currently considered the abortive pharmacological agent of choice, but the recommended dose is only 2 per day and it is very expensive. Alternative acute treatments may be considered for patients with more than 2 attacks a day, patients with intolerable adverse effects or any contraindications to sumatriptan, and patients with extended periods of headache or a chronic syndrome. Very young or very old patients should also receive an individually tailored acute treatment. There is at present only limited experience in the management of patients in the latter age groups. It appears rational that pregnant and nursing women with a period of cluster headache should not be given sumatriptan. In most of the patients groups mentioned, inhalation of 100% oxygen is recommended as the acute therapy of use. (Ekbom 2002)
Oxygen inhalation is an effective method which can be safely used for the repetitive acute treatment of cluster headache. The great advantage with oxygen is that it has no established adverse effects and is much lower in cost then subcutaneous injection of sumatriptan (Ekbom 2002) or nasal zolmitriptan. Oxygen does not interact with and can be readily combined with other abortive and preventative medications and procedures. It can be used several times a day as opposed to injectable sumatriptan or inhaled zolmitriptan which can only be used up to a maximum of two times a day respectively. (Matharu 2003.) Inhaled oxygen can also provide an effective means of therapy for those cluster headache sufferers who are phobic regarding needles or self injection.
The cost per year for oxygen as an abortive for even a continuous chronic cluster headache sufferer is measured in a few thousand dollars versus the many ten's of thousands of dollars per year which subcutaneously injected sumatriptan or inhaled zolmitriptan can cost an insurance carrier or patient without insurance, or, a patient with a high co-pay, either for an episodic sufferer or in particular for a chronic sufferer. Should a method of oxygen use be identified that can significantly improve the efficacy of oxygen in aborting a cluster headache it would further enhance the use of this lower cost alternative to subcutaneously injected sumatriptan or inhaled zolmitriptan.
Accordingly, the need exists to provide a method of using oxygen which is relatively low in cost and affordable with or without insurance coverage by the majority of cluster headache sufferers, which can be safely used multiple times per day with no known adverse effects and which can provide an effective and significantly improved abortive method compared to existing standard of care continuous flow oxygen methods using a non-breathing bag system and which can reduce the need for sole or co-use of very high cost sumatriptan injection or inhaled zolmitriptan.